Lymphoma Control Better Goal Than Remission

Ingrid Hein

June 20, 2019

Getting lymphoplasmacytic lymphoma under control might be a better objective than complete remission, delegates heard here at the International Waldenstrom's Macroglobulinemia Foundation 2019 Forum in Philadelphia.

Complete responses are uncommon in Waldenstrom's macroglobulinemia, even with targeted therapy, because when you look at the bone marrow of a patient, "it's not just one type of cell we're going after," said Steven Treon, MD, PhD, from Harvard Medical School at the Dana-Farber Cancer Institute in Boston.

"Merely trying to put myriad drugs together and throwing them at the patient with the hope of complete remission is not necessarily the end line if we're creating other problems along the way," he said. "That's why these debates are genuine and important."

We try to avoid treating with too many drugs, especially in patients who are younger, he explained, and four cycles of treatment have been shown to be just as effective as six. But "what's younger?" he asked. The average person with WM is 70 years old.

"Anyone younger than the oncologist is younger," he joked, drawing chuckles from the audience.

Results from a multicenter phase 2 study of 63 patients with previously treated Waldenstrom's macroglobulinemia, in which the response rate was 62% — 11% achieved very good partial responses and 51% achieved partial responses — led to the approval of ibrutinib by the US Food and Drug Administration (N Engl J Med. 2015;372:1430-1440).

Ibrutinib Effective, Combinations Needed for Some Mutations

Five years after that study, 60% of patients are still in remission. "Some had nine previous therapies," Treon reported. "The important thing is that few therapies have an action available for mutations of Waldenstrom's."

Other drugs are emerging to better target the several mutations that require different treatments, but knowing which ones are needed, and when, is still not clear.

Although ibrutinib as a primary therapy for patients with untreated WM is highly active, durable, and safe, Treon and his colleagues showed that rates of major response were better in patients with wild-type CXCR4 than those with CXCR4 mutations (94% vs 71%), as were rates of partial response (31% vs 7%) and time to major response (1.8 vs 7.3 months; P = .01) (J Clin Oncol. 2018;36;2755-2761).

The discovery of MYD88 mutations, found in 93% to 97% of WM patients, and the emergence of whole-genome sequencing have made it much easier to identify mutations and where the problems are, Treon explained.

Still, looking for one "mistake" in the MYD88 gene, which has 2 billion DNA molecules, is "literally like looking for needle in a haystack," he pointed out.

You can use peripheral blood to check for the mutation, but you have to do it before the patient has had any therapy or it's "going to be hard," he noted.

"Ibrutinib is a very good drug, but we're starting to see resistance," he said.

A clinical trial looking at ibrutinib in combination with an oral ERK inhibitor that targets mutated cells is currently underway. And results from a WM trial presented at the 2018 ASCO annual meeting showed that acalabrutinib, targeting Bruton's tyrosine kinase (BTK) in treatment-naive or relapsed/refractory WM, is "highly effective" and has "limited toxicity" (abstract 7501).

Because it can take several drugs to target the different molecules, toxicity becomes an issue as therapies pile up on one another.

Knowing the MYD88 and CXCR4 mutation status of a patient helps us determine the therapeutic approach needed today and what we should plan for tomorrow, Treon explained.

That's why it is so important to find a way, other than bone marrow biopsies, to look for MYD88 mutations. "If we're going to personalize medicine, we have to get this right," he said.

"Genomic mistakes are a moving target. We need personalized medicine," he added. We need to better understand "what happens to these clones over time with different therapeutics."

After the presentation, an audience member asked Treon whether ibrutinib is mutagenic.

"No," he responded. "As best as we can tell, these mutations are pre-existing." As you apply the selective pressure of the drug on the targets, "these are the clones that are breaking through and growing." These are the "one to a million clones; we don't have the ability to test out those kind of mutations at that frequency," he explained, "but it's unlikely the drugs are mutagenic"

Treon has disclosed no relevant financial relationships.

International Waldenstrom's Macroglobulinemia Foundation (IWMF) 2019 Forum. Presented June 8, 2019.

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